Muscarinic receptor antagonists

ABSTRACT

A compound of the formula ##STR1## wherein X, R 1 , R 2 , R 3 , R.sup. 4 , Y, m and n are defined herein are useful as muscarinic receptor antagonists.

This is a continuation of application Ser. No. 07/877,166, filed asPCT/EP90/02044, Nov. 28, 1990, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to certain benzodiazepinone derivatives. Thecompounds of the invention are muscarinic receptor antagonists which areselective for smooth muscle muscarinic sites over cardiac muscarinicsites and which do not have any significant antihistaminic activity.Thus the compounds are useful in the treatment of diseases associatedwith altered motility and/or tone of smooth muscle which can, forexample, be found in the gut, trachea and bladder. Such diseases includeirritable bowel syndrome, divertitular disease, urinary incontinence,oesophageal achalasia and chronic obstructive airways disease.

SUMMARY OF THE INVENTION

According to the invention there are provided compounds of the formula:##STR2## and their pharmaceutically acceptable salts, wherein X is N orwhere

R⁴ is H, halo or C₁ -C₄ alkyl;

R¹ is H or C₁ -C₄ alkyl;

R² is H or C₁ -C₄ alkyl;

Y is a direct link, O or S;

m is an integer of from 1 to 4;

n is 2 or 3; and

R³ is 1- or 2-naphthyl or a group of the formula: ##STR3## where

R⁵ and R⁶ are each independently H, C₁ -C₄ alkyl, C₁ -C₄

alkoxy , --(CH2)_(q),OH, halo, trifluoromethyl cyano,

--(CH₂)_(q) NR7R⁸, --OCO(C₁ -C₄ alkyl) --SO₂ NH₂ or --CONR⁹ R¹⁰, whereeither R⁷ and R⁸ are each independently H or C₁ -C₄ alkyl, or

R⁷ is H and R⁸ is --SO₂ (C₁ -C₄ alkyl), --CONR⁹ R¹⁰ ;

--CO(C₁ -C₄ alkyl) or --SO₂ NH₂ ;

R⁹ and R¹⁰ are each independently H or C₁ -C₄ alkyl;

q is 0, 1 or 2;

Z and Z¹ are each independently 0 or CH₂ ;

p is 1, 2 or 3; and "Het" is pyridyl, pyrazinyl or thienyl.

Preferably, R¹ is H. X is preferably N or CH. m is preferably 1, 2 or 3.n is preferably 2. R² is preferably methyl. Y is preferably a directlink or 0.

R³ is preferably 2-naphthyl, pyridyl or a group of the formula: ##STR4##where R⁵ and R⁶ are each independently H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,halo (preferably chloro), trifluoromethyl, cyano or C₁ -C₄alkanesulphonamido, and Z¹ is 0 or CH₂.

The pharmaceutically acceptable salts of the compounds of formula (I)include acid addition salts such as the hydrochloride, hydrobromide,sulphate or bisulphate, phosphate or hydrogen phosphate, acetate,berylate, citrate, fumarate, gluconate, lactate, maleate, mesylate,succinate and tartrate salts. For a more comprehensive list ofpharmaceutically acceptable salts see, for example, the Journal ofPharmaceutical Sciences, Vol. 66, No. 1, January 1977, pages 1-19. Thesesalts can be prepared conventionally, e.g. by mixing a solution of thefree base and the acid in a suitable solvent, e.g. ethanol, andrecovering the acid addition salt either as a precipitate, or byevaporation of the solution.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula (I) can be prepared by the followingroutes:

Route A

This involves the reaction of a benzodiazepinone of the formula (II)with an alkylating agent of the formula (III), as follows: ##STR5##

In the above, X, Y, R¹, R², R³, m and n are as defined for formula (I)and Q is a leaving group, e.g. Br, Cl, C₁ -C₄ alkanesulfonyloxy (e.g.methanesulfonyloxy), benzenesulfonyloxy, toluenesulfonyloxy (e.g.p-toluenesulfonyloxy) or trifluoromethanesulfonyloxy. Preferably, Q isCl, Br, I or methanesulfonyloxy. Most preferably, Q is Br.

The reaction is preferably carried out in the presence of an acidacceptor such as sodium hydrogen carbonate, sodium or potassiumcarbonate, triethylamine or pyridine, and in a suitable organic solvent,e.g. acetonitrile, at up to the reflux temperature. Reactiontemperatures of 60°-120° C. are generally desirable and it is mostconvenient to carry out the reaction under reflux. Iodo is often aparticularly suitable leaving group but since the starting materials(III) are sometimes most conveniently available as chlorides or bromidesthe reaction can also be carried out using the compound (III) as achloride or bromide but in the presence of an iodide such as sodium orpotassium iodide.

The starting materials of the formula (II) are either known compounds orcan be prepared by conventional procedures, see e.g. J. Med. Chem.,1963, 6, 255, German Patentschrift no. 1,936,670, and British patent no.1,581,500.

The starting materials of the formula (III) are again either knowncompounds or can be prepared conventionally: the preparation of anynovel compounds of the formula (III) used in the Examples is in factdescribed in the following Preparations section.

Route B

This route can be represented schematically as follows: ##STR6##

R¹, R², R³, X, Y, m and n are as defined for formula (I) and Q is aleaving group such as is described in Route A. The reaction can becarried out similarly to Route A. Clearly use of the compound (V) willproduce compounds (I) in which m is 2.

When m is 2, a mixture of the 11-(3-chloropropionyl) and 11-acryloylcompounds can be used: such a mixture is prepared in Preparation 1.Chromatographic techniques to separate the compounds can of course beused.

The compounds (IV) and (V) are either known (see e.g. GB 1,581,500 andDT-PS 1,936,670) or can be prepared by conventional techniques such asthose described in the following Preparations 1 to 3.

The compounds (VI) are either known or can be prepared conventionally asis illustrated in the following Preparations.

The selectivity of the compounds as muscarinic receptor antagonists canbe measured as follows.

Male guinea pigs are sacrificed and the ileum, trachea, bladder andright atrium are removed and suspended in physiological salt solutionunder a resting tension of 1 g at 32° C. aerated with 95% O₂ and 5% CO₂.Contractions of the ileum, bladder and trachea are recorded using anisotonic (ileum) or isometric transducer (bladder and trachea). Thefrequency ef contraction of the spontaneously beating right atrium isderived from isometrically recorded contractions.

Dose-response curves to either acetylcholine (ileum) or carbachol(trachea, bladder and right atrium) are determined using a 1-5 minutecontact time for each dose of agonist until the maximum response isachieved. The organ bath is drained and refilled with physiological saltsolution containing the lowest dose of the test compound. The testcompound is allowed to equilibrate with the tissue for 20 minutes andthe agonist dose-response curve is repeated until the maximum responseis obtained. The organ bath is drained and refilled with physiologicalsalt solution containing the second concentration of test compound andthe above procedure is repeated. Typically four concentrations of thetest compound are evaluated on each tissue.

The concentration of the test compound which causes a doubling of theagonist concentration required to produce the original response isdetermined (pA₂ value - Arunlakshana and Schild (1959), Brit. J.Pharmacol., 14, 48-58). Using the above analytical techniques, tissueselectivity for muscarinic receptor antagonists is determined.

Activity against agonist induced bronchoconstriction or gut or bladdercontractility in comparison with changes in heart rate is deterimined inthe anaesthetised dog. Oral activity is assessed in the conscious dogdetermining compound effects on, for example, heart rate, pupil diameterand gut motility.

Compound affinity for other cholinergic sites is assessed in the mouseafter either intravenous or intraperitoneal administration. Thus, thedose which causes a doubling of pupil size is determined as well as thedose which inhibits the salivation and tremor responses to intravenousoxotremorine by 50%.

For administration to man in the curative or prophylactic treatment ofdiseases associated with the altered motility and/or tone of smoothmuscle, such as irritable bowel syndrome, diverticular disease, urinaryincontinence, oesophageal achalasia and chronic obstructive airwaysdisease, oral dosages of the compounds will generally be in the range offrom 3.5 to 350 mg daily for an average adult patient (70 kg). Thus fora typical adult patient, individual tablets or capsules will typicallycontain from 1 to 250 mg of active compound, in a suitablepharmaceutically acceptable vehicle or carrier for administration singlyor in multiple doses, once or several times a day. Dosages forintravenous administration will typically be within the range 0.35 to 35mg per single dose as required. In practice the physician will determinethe actual dosage which will be most suitable for an individual patientand it will vary with the age, weight and response of the particularpatient. The above dosages are exemplary of the average case but therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

For human use, the compounds of the formula (I) can be administeredalone, but will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, theymay be administered orally in the form of tablets containing suchexcipients as starch or lactose, or in capsules or ovules either aloneor in admixture with excipients, or in the form of elixirs ofsuspensions containing flavouring or colouring agents. They may beinjected parenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances,for example, enough salts or glucose to make the solution isotonic withblood.

In a further aspect the invention provides a pharmaceutical compositioncomprising a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablediluent or carrier.

The invention also includes a compound of the formula (I) or apharmaceutically acceptable salt thereof, for use as a medicament,particularly for use in the treatment of irritable bowel syndrome.

The invention further includes the use of a compound of the formula (I),or of a pharmaceutically acceptable salt thereof, for the manufacture ofa medicament for the treatment of diseases associated with the alteredmotility and/or tone of smooth muscle, such as irritable bowel syndrome,diverticular disease, urinary incontinence, oesophageal achalasia andchronic obstructive airways disease.

The invention yet further includes a method of treatment of a humanbeing to cure or prevent a disease associated with the altered motilityand/or tone of smooth muscle, such as irritable bowel syndrome, whichcomprises treating said human being with an effective amount of acompound of the formula (I), or a pharmaceutically acceptable salt orcomposition thereof.

The Examples illustrate the preparation of the compounds of the formula(I), and the Preparations illustrate the preparation of certain of thestarting materials used in the preceding Examples.

EXAMPLE 1 5- {3-[N-(4-Methylphenethyl)-N-methylamino]propionyl}-10,11-dihydrodibenzo [b,e][1,4]diazepin-11-one ##STR7##

A mixture of 5-(3-methylaminopropionyl)-10,11-dihydrodibenzo[b,e][1,4]diazepin-11-one (0.20 g) (J. Med. Chem., 1963, 6, 255),4-methylphenethyl bromide (0.14 g) and sodium hydrogen carbonate (60 mg)in acetonitrile (20 ml) was heated under reflux for 16 hours andevaporated. The residue was partitioned between water anddichloromethane and the organic layer washed with brine, dried overMgSO₄ and evaporated. The residue was purified by chromatography onsilica using dichloromethane plus 0-20% methanol as eluant. Appropriatefractions were combined and evaporated and the residue crystallised fromether to give the title compound as a colourless solid, 60 mg (21%).

Analysis %: Found: C,75.1; H,6.5; N,10.0; C₂₆ H₂₇ N₃ O₂ requires:C,75.5; H,6.6; N,10.2.

EXAMPLES 2-4

The following tabulated examples of the general formula: ##STR8## wereprepared as described for Example 1 by reacting5-(3-methylaminopropionyl)-1O,11-dihydrodibenzo[b,e][1,4]-diazepin-11-onewith a slight excess of the appropriate 2-arylethyl bromide in thepresence of sodium hydrogen carbonate using acetonitrile as the solvent.

    ______________________________________                                        Ex-            Form                                                           ample R.sup.5  characterised                                                                             Analysis %                                         ______________________________________                                        2     --H      Colourless  Found: C,74.7; H,6.4; N,10.3;                                     solid,      C.sub.25 H.sub.25 N.sub.3 O.sub.2 requires                        m.p. 63-64° C.                                                                     C,75.2; H,6.3; N,10.5.                             3     --Cl     Colourless  Found: C,69.5; H,5.8; N,9.4;                                      solid,      C.sub.25 H.sub.24 ClN.sub.3 O.sub.2 requires:                     m.p. 68-70° C.                                                                     C,69.2; H,5.6; N,9.7.                              4     --OCH.sub.3                                                                            Colourless  Found: C,72.5; H,6.5; N,10.1;                                     oil.        C.sub.26 H.sub.27 N.sub.3 O.sub.3 requires:                                   C,72.7; H,6.3; N,9.8.                              ______________________________________                                    

EXAMPLE 55,11-Dihydro-11-{2-[N-(4-methoxyphenethyl)-N-methylamino]acetyl}-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one##STR9##

A mixture of 11-chloroacetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-one (288 mg) (German patent 1,936,670),N-(4-methoxyphenethyl)methylamine (182 mg) and sodium hydrogen carbonate(92 mg) in acetonitrile (25 ml) was heated under reflux for 16 hours andevaporated. The residue was partitioned between 2M aqueous sodiumhydrogen carbonate solution and dichloromethane and the organic layerwashed with brine, dried over MgSO₄ and evaporated. The residue waspurified by chromatography on silica using dichloromethane plus 0-10%methanol as eluant. Appropriate fractions were combined and evaporatedand the residue crystallised from ethyl acetate to give the titlecompound as a colourless solid, 216 mg (52%).

Analysis %: Found: C,69.2; H,5.8; N,13.5; C₂₄ H₂₄ N₄ O₃ requires:C,69.2; H,5.8; N,13.4.

EXAMPLES 6-10

The following tabulated Examples of the general formula: ##STR10## wereprepared as described for Example 5 by reacting the appropriate5-chloroacyl-10,11-dihydrodibenzo[b,e][1,4]diazepin6-one with oneequivalent of the appropriate arylalkylmethylamine in the presence oftwo equivalents of sodium hydrogen carbonate using acetonitrile as thesolvent. The product of Example 10 was characterised as containing 0.10equivalents of dichloromethane (derived from the chromatography) whilethe product of Example 8 was characterised as a hydrate. The preparationof the starting material for Examples 6-8 is described in Preparation 2while the preparation of the starting material for Example 9 isdescribed in Preparation 3. The starting material for Example 10 wasprepared according to German patent no. 1,936,670.

    __________________________________________________________________________    Example              Form                                                     No.  R.sup.1                                                                          m R.sup.3    characterised                                                                          Analysis %                                      __________________________________________________________________________     6   H  3                                                                                          Colourless gum                                                                         Characterised by .sup.1 H-N.M.R.                                              (CDCl.sub.3)δ=7.1-8.3(m, 8H); 7.13(d,                                   J.sup.3 =8Hz, 2H); 6.83(d, J=8Hz, 2H);                                        3.81(s, 3H); 2.1-2.8 (m, 8H); 2.24(s, 3H);                                    1.65-1.95(m, 2H).                                7   H  3                                                                                ##STR11## Colourless foam                                                                        Found: C, 69.7; H, 5.9; H, 9.4; Calculated                                    for C.sub.26 H.sub.26 ClN.sub.3 O.sub.2 :                                     C, 69.3; H, 5.8; N, 9.4.                         8   H  3                                                                                ##STR12## Colourless oil; hydrate                                                                Found: C, 71.2; H, 6.5; N, 9.1; Calculated                                    for C.sub.28 H.sub.29 N.sub.3 O.sub.3.H.sub.                                  2 O: C, 71.0; H, 6.6; N, 8.8.                    9   Me 3                                                                                ##STR13## Colourless oil                                                                         Found: C, 73.5; H, 7.2; N, 9.0; Calculated                                    for C.sub.28 H.sub.31 N.sub.3 O.sub.3 : C,                                    73.5; H, 6.8; N, 9.2.                           10   Me 2                                                                                ##STR14## Colourless oil containing 0.10 equivalents of                                 dichloromethane                                                                        Found: C, 71.9; H, 6.6; N, 9.3; Calculated                                    for C.sub.27 H.sub.29 N.sub.3 O.sub.3.0.1                                     CH.sub.2 Cl.sub.2 : C, 72.0; H, 6.5; N,         __________________________________________________________________________                                  9.3.                                        

EXAMPLE 115,11-Dihydro-11-[3-[N-(4-methoxyphenethyl)-N-methylamino]-propionyl-6H-pyrido[%,3-b][1,4]benzodiazepin-6-one##STR15##

A mixture of11-acryloyl-5,11-dihydro-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one (185mg) (see Preparation 1) and N-(4-methoxyphenethyl)methylamine (127 mg)in dioxane (15 ml) was heated under reflux for 4 hours and evaporated.The residue was partitioned between water and dichloromethane and theorganic layer dried over MgSO₄ and evaporated. The residue was purifiedby chromatography on silica using dichloromethane plus 0-2% methanol aseluant. Appropriate fractions were combined and evaporated to give thetitle compound as a pale yellow solid, 182 mg (60%), m.p. 163°-164° C.,which was characterised as a hemihydrate.

Analysis %:

Found: C,68.0; H,6.2; N,12.6;

C₂₅ H₂₆ N₄ O₃.O.5 H₂ O requires: C,68.3; H,6.2; N,12.7.

EXAMPLES 12-21

The following tabulated Examples of the general formula: ##STR16## wereprepared as described for Example 11 by reacting11-acryloyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (seePreparation 1) with a slight excess of the appropriatearylalkylmethylamine in the presence of excess sodium hydrogen carbonateusing acetonitrile as solvent. The products of Examples 12, 13, 16, 18and 19 were characterised as hemihydrates.

    __________________________________________________________________________    Example No                                                                           R.sup.3     Form characterised                                                                      Analysis %                                       __________________________________________________________________________    12                                                                                               Colourless solid, m.p. 82-83° C., hemihydrate                                    Found: C, 69.8; H, 5.5; N, 14.9; C.sub.25                                     H.sub.23 N.sub.5 O.sub.2.0.5 H.sub.2 O                                        requires: C, 69.1; H, 5.6; N, 16.1.              13                                                                                    ##STR17##  Colourless solid, m.p. 170° C., hemihydrate                                      Found: C, 59.8; H, 4.6; N, 11.4; C.sub.24                                     H.sub.22 Cl.sub.2 N.sub.4 O.sub.2.0.5                                         H.sub.2 O requires: C, 60.2; H, 4.8; N,                                       11.7.                                            14                                                                                    ##STR18##  Colourless solid, m.p. 66° C.                                                    Found: C, 73.4; H, 6.8; N, 12.7; C.sub.27                                     H.sub.30 N.sub.4 O.sub.2 requires: C, 73.3;                                   H, 6.8; N, 12.7.                                 15                                                                                    ##STR19##  Colourless solid, m.p. 66-68° C.                                                 Found: C, 64.2; H, 4.9; N, 12.0; C.sub.25                                     H.sub.23 F.sub.3 N.sub.4 O.sub.2 requires:                                    C, 64.1; H, 4.9; N, 12.0.                        16                                                                                    ##STR20##  Colourless solid, m.p. 70-72° C., hemihydrate                                    Found: C, 68.7; H, 6.3; N, 12.3; C.sub.26                                     H.sub.28 N.sub.4 O.sub.3.0.5 H.sub.2 O                                        requires: C, 68.7; H, 6.4; N, 12.3.              17                                                                                    ##STR21##  Colourless solid, m.p. 168-170° C.                                               Found: C, 73.4; H, 5.8; N, 12.2; C.sub.28                                     H.sub.26 N.sub.4 O.sub.2 requires: C, 73.2;                                   H, 5.9; N, 12.2.                                 18                                                                                    ##STR22##  Colourless solid, m.p. 69-71° C., hemihydrate                                    Found: C, 65.4; H, 5.3; N, 12.8; C.sub.24                                     H.sub.23 ClN.sub.4 O.sub.2.0.5 H.sub.2 O                                      requires: C, 64.9; H, 5.4; N, 12.6.              19                                                                                    ##STR23##  Colourless solid, m.p. 155-157° C., hemihydrate                                  Found: C, 69.5; H, 6.3; N, 12.3; C.sub.26                                     H.sub.26 N.sub.4 O.sub.3.0.5 H.sub.2 O                                        requires: C, 69.2; H, 6.0; N, 12.4.              20                                                                                    ##STR24##  Colourless solid, m.p. 63-65° C.                                                 Found: C, 68.9; H, 5.9; N, 17.4; C.sub.23                                     H.sub.23 N.sub.5 O.sub.2 requires: C, 68.8;                                   H, 5.8; N, 17.4.                                 21                                                                                    ##STR25##  Colourless solid, m.p. 141-142° C.                                               Found: C, 72.5; H, 6.4; N, 13.4; C.sub.25                                     H.sub.26 N.sub.4 O.sub.2 requires: C, 72.4;                                   H, 6.3; N, 13.5.                                 __________________________________________________________________________

EXAMPLES 22-30

The following tabulated Examples of the general formula: ##STR26## wereprepared as described for Example 11 by reacting a mixture of11-acryloyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido[2,B-b][1,4]-benzodiazepin-6-one (see Preparation 1) with a slight excess of theappropriate arylalkylmethylamine in the presence of excess sodiumhydrogen carbonate using acetonitrile as solvent. The products ofExamples 23-28 were characterised as hemihydrates. TheN-(4-methanesulphonamidophenethyl)methylamine used in Example 30 wasprepared as described in EP-A-245,997.

    __________________________________________________________________________    Example                                                                       No.  Y    R.sup.3      n Form characterised                                                                      Analysis %                                 __________________________________________________________________________    22   a direct link                                                                                   2 Colourless solid, m.p. 163-164° C.                                               Found: C, 72.1; H, 6.3; N, 13.7;                                              C.sub.25 H.sub.26 N.sub.4 O.sub.2                                             requires: C, 72.4; H, 6.3; N, 13.5.        23   a direct link                                                                       ##STR27##   2 Colourless solid, m.p. 144-145° C.                                     hemihydrate                                                                             Found: C, 71.1; H, 6.3; N, 13.1;                                              C.sub.25 H.sub.26 N.sub.4 O.sub.2.0.5                                         H.sub.2 O requires: C, 70.9; H, 6.4;                                          N, 13.2.                                   24   a direct link                                                                       ##STR28##   2 Colourless solid, m.p. 171-172° C.,                                    hemihydrate                                                                             Found: C, 72.3; H, 6.5; N, 12.3;                                              C.sub.27 H.sub.28 N.sub.4 O.sub.2.0.5                                         H.sub.2 O requires: C, 72.1; H, 6.5;                                          N, 12.5.                                   25   0                                                                                   ##STR29##   2 Colourless solid, m.p. 67° C., hemihydrate                             .         Found: C, 68.0; H, 5.9; N, 13.4;                                              C.sub.24 H.sub.24 N.sub.4 O.sub.3.0.5                                         H.sub.2 O requires: C, 67.8; H, 5.9;                                          N, 13.2.                                   26   a direct link                                                                       ##STR30##   2 Colourless solid, m.p. 150-151° C.,                                    hemihydrate                                                                             Found: C, 65.3; H, 5.2; N, 12.6;                                              C.sub.24 H.sub.23 ClN.sub.4 O.sub.2.0.5                                        H.sub.2 O requires: C, 64.9; H, 5.4;                                         N, 12.6.                                   27   a direct link                                                                       ##STR31##   2 Colourless solid, m.p. 144° C., hemihydrat                             e         Found: C, 70.6; H, 6.0; N, 13.5;                                              C.sub.24 H.sub.24 N.sub.4 O.sub.2. 0.5                                        H.sub.2 O requires: C, 70.4; H, 6.1;                                          N, 13.7.                                   28   a direct link                                                                       ##STR32##   3 Colourless solid, m.p. 48-50° C.,                                      hemihydrate                                                                              Found: C, 68.6; H, 6.1; N, 12.3;                                             C.sub.26 H.sub.28 N.sub.4 O.sub.3.0.5                                         H.sub.2 O requires: C, 68.8; H, 6.4;                                          N, 12.3.                                   29   0                                                                                   ##STR33##   3 Colourless solid, m.p. 65-67° C.                                                 Found: C, 69.2; H, 6.1; N, 13.0;                                              C.sub.25 H.sub.26 N.sub.4 O.sub.3                                             requires: C, 69.7; H, 6.1; N, 13.0.        30   a direct link                                                                       ##STR34##   2 Colourless solid, m.p. 814-185° C.                                               Found: C, 60.7; H, 5.4; N, 14.1;                                              C.sub.25 H.sub.27 N.sub.5 O.sub.4 S                                           requires: C, 60.8; H, 5.5; N,              __________________________________________________________________________                                       14.2.                                  

The following Preparations illustrate the preparation of certain of thestarting materials used in the previous Examples.

Preparation 111-Acryloyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and amixture thereof with the corresponding 11-(3-chloro-propionyl) compound##STR35##

Solutions of 3-chloropropionyl chloride (6.3 g) in dioxane (60 ml) andtriethylamine (8.4 g) in dioxane (60 ml) were added simultaneously to arefluxing suspension of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (9.45 g - see DT-PS 1179943) in dioxane(300 ml) and the mixture was heated under reflux for 6 hours andevaporated to give a mixture of the two title compounds in which theacryloyl compound predominated. Crude mixtures of the 11-acryloyl and11-(3-chloropropionyl) compounds prepared using this procedure were usedin Examples 22-30. The residue was purified by chromatography on silicausing dichloromethane plus 0-2% methanol as eluant. Appropriatefractions were combined and evaporated to give the title 11-acryloylcompound as a colourless solid, 3.2 g, (27%) which was used directly inExamples 11-21.

Preparation 2 5- (4-Chlorobutyryl)-10,11-dihydrodibenzo[b,e][1,4]diazepin-11-one ##STR36##

A mixture of 4-chlorobutyryl chloride (3.5 g) and10,11-dihydrodibenzo[b,e][1,4]diazepin-11-one (4.2 g) (J. Med. Chem.,1963, 6, 767) in acetone (90 ml) was heated under reflux for 8 hours andevaporated. The residue was purified by chromatography on silica usinghexane plus 0-100% dichloromethane as eluant. Appropriate fractions werecombined and evaporated and the residue triturated withhexane/dichloromethane to give the title compound as a colourless solid,1.62 g (26%), m.p. 151°-152° C.

Analysis %: Found: C,64.6; H,4.7; N,8.8; C₁₇ H₁₅ ClN₂ O₂ requires:C,64.9; H,4.8; N,8.9.

Preparation 35-(4-Chlorobutyryl)-10,11-dihydro-10-methyldibenzo[b,e][1,4]-diazepin-11-one##STR37##

A mixture of 4-chlorobutyryl chloride (0.88 g) and10,11-dihydro-10-methyldibenzo[b,e][1,4]diazepin-10-one (1.12 g) (J.Med. Chem., 1963, 6, 767) in acetone (25 ml) was heated under reflux for4 hours and evaporated. The residue was dissolved in ethyl acetate andthe solution washed with 10% aqueous sodium hydrogen carbonate solution,dried over Na₂ SO₄ and evaporated. The residue was purified bychromatography on silica using hexane plus 0-100% dichloromethane aseluant. Appropriate fractions were combined and evaporated to give thetitle compound as a colourless oil, 1.10 g (67%).

Analysis %: Found: C,65.9; H,5.4; N,8.4; C₁₈ H₁₇ ClN₂ O₂ requires:C,65.7; H,5.2; N,8.5.

Preparation 4 N-(3-Methylphenethyl)methylamine ##STR38##

A mixture of 3-methylphenethyl bromide (2.22 g) and 33% ethanolicmethylamine solution (30 ml) was heated in a bomb at 80° C. for 16 hoursand evaporated. The residue was partitioned between water anddichloromethane and the organic layer dried over MgSO₄ and evaporated.The residue was purified by 421 chromatography on silica usingdichloromethane plus 0-10% methanol as eluant. Appropriate fractionswere combined and evaporated to give the title compound as a colourlessoil, 0.44 g (27%), which was used directly in the preparation of Example21 without characterisation.

Preparations 5-10

The following tabulated Preparations of the general formula: ##STR39##were prepared as described for Preparation 4 by reacting the appropriatearylethyl bromide with 33% ethanolic methylamine solution. In each casethe product was characterised by its ¹ H-N.M.R. spectrum. Thepreparation of the starting materials for Preparations 7, 10, 6 and 8are described in Preparations 11, 12, 13 and 14. The product fromPreparation 10 was obtained as a colourless solid.

    __________________________________________________________________________    Preparation No.                                                                       R.sup.3     Form characterised                                                                      .sup.1 H-N.M.R.                                 __________________________________________________________________________                        Yellow oil                                                                              .sup.1 H-N.M.R. (CDCl.sub.3)δ=7.59(d,                                   J=8Hz, 2H); 7.30(d, J.sup.3 =8Hz, 2H);                                        2.86(s, 4H); 2.63(s, 3H); 1.22(s, 1H).          6                                                                                      ##STR40##  Yellow oil                                                                              .sup.1 H-N.M.R. (CDCl.sub.3)δ=7.58(d,                                   J=8Hz, 2H); 7.36(d, J.sup.3 =8Hz, 2H);                                        2.85(s, 4H); 2.44(s, 3H); 1.37(s, 1H).          7                                                                                      ##STR41##  Dark oil  .sup.1 H-N.M.R. (CDCl.sub.3)δ=6.8-7.4(                                  m, 3H); 2.60-3.05(m, 4H); 2.43(s, 3H);                                        2.05(t, J=7Hz, 2H); 1.90(s, 1H).                8                                                                                      ##STR42##  Yellow oil                                                                              .sup.1 H-N.M.R. (CDCl.sub.3)δ=6.97-7.0                                  8(m, 2H); 6.79(d, J=8Hz, 1H); 4.92(broad s,                                   H); 3.81(s, 3H); 2.88-3.00(m, 4H); 2.57(s,                                    3H); 2.21(s, 3H).                               9                                                                                      ##STR43##  Yellow oil                                                                              .sup.1 H-N.M.R. (CDCl.sub.3)δ=7.06-7.2                                  4(m, 4H); 2.80-3.00(m, 5H); 2.46(s, 3H);                                      2.06 (broad s, 1H); 1.24(d, J=7Hz, 6H).         10                                                                                     ##STR44##  Colourless solid, m.p. 153-155° C.                                               .sup.1 H-N.M.R. (CDCl.sub.3)δ=7.11(s,                                   1H); 6.99 (d, J=8Hz, 1H); 6.77(d, J=8Hz,                                      1H); 4.58(t, J=7Hz, 2H); 3.13(s, 4H); 3.11                                    (t, J=7Hz, 2H); 1.13(broad s,                   __________________________________________________________________________                                  1H).                                        

Preparation 11 5-(2-Bromoethyl)indane ##STR45##

Phosphorus tribromide (3.5 ml) was added, dropwise, to a solution of5-(2-hydroxyethyl)indane (14.0 g) (FR-A-2139628) in carbon tetrachloride(100 ml). The mixture was stirred at room temperature for 0.5 hour andthen heated under reflux for 2 hours. Ice (100 g) was added and themixture partitioned between dichloromethane and 10% aqueous sodiumcarbonate solution. The layers were separated and the aqueous layerextracted wilth dichloromethane (2×100 ml). The combined dichloromethaneextracts were dried (MgSO4) and concentrated in vacuo to give an oilwhich was purified by column chromatography on silica eluting withdichloromethane. The product-containing fractions were combined andconcentrated in vacuo to give the title compound as a colourless oil,yield 10.5 g.

¹ H N.M.R. (CDCl₃) δ=7.00-7.30 (m, 3H); 3.60 (m, 2H); 3.20 (m, 2H);2.85-3.00 (m, 4H); 2.05-2.20 (m, 2H).

Preparation 12-14

The following tabulated Preparations of the general formula: ##STR46##were prepared as described for Preparation 11 by reacting theappropriate arylethyl alcohol with phosphorus tribromide in carbontetrachloride solution. In each case the product was obtained as ayellow oil which was characterised by its ¹ H-N.M.R. spectrum. Thepreparation of the starting materials for Preparations 12 and aredescribed in Preparations 15 and 16, respectively.

    __________________________________________________________________________    Preparation No.                                                                       R.sup.3      .sup.1 H-N.M.R. (CDCl.sub.3), δ                    __________________________________________________________________________    12                                                                                                 7.10(s, 1H); 6.95-7.00(d, 1H); 6.70-6.80(d, 1H);                              4.60(t, J= 7Hz, 2H); 3.55(t, J=7Hz, 2H); 3.20(t,                              J=7Hz, 2H); 3.12(t, J=7Hz, 2H).                          13                                                                                     ##STR47##   7.62(d, J=8Hz, 2H); 7.39(d, J=8Hz, 2H); 3.63(t,                               J=7Hz, 2H); 3.24(t, J=7Hz, 2H).                          14                                                                                     ##STR48##   7.01-7.07(m, 2H); 6.79(d, J=8Hz, 2H); 3.84(s, 3H);                            3.58(t, J=7Hz, 2H); 3.10(t, J=7Hz, 2H); 2.22(s,          __________________________________________________________________________                         3H).                                                 

Preparation 15 5 -(2-Hydroxyethyl)-2,3-dihydrobenzofuran ##STR49##

A solution of (2,3-dihydrobenzofuran-5-yl)acetic acid (4.9 g - seeEP-A-132130) in anhydrous tetrahydrofuran (50 ml) was added dropwiseover 10 minutes to a stirred suspension of lithium aluminium hydride(1.57 g) in anhydrous tetrahydrofuran (50 ml) at 0° C. The mixture wasallowed to warm to room temperature and stirred for 1 hour. Water (1.5ml) was cautiously added dropwise followed by 10% aqueous sodiumhydroxide (1.5 ml) and, finally, water (4.5 ml). The mixture wasfiltered and the inorganic salts washed with ethyl acetate (2×50 ml).The filtrate and washings were combined and concentrated in vacuo togive the title compound as an oil, yield 3.3 g.

¹ H N.M.R. (CDCl₃)δ-7.10 (s, 1H); 7.00 (d, J=8Hz, 1H); 6.75 (m, 1H);4.55-4.65 (m, 2H); 3.75-3.90 (m, 2H); 3.15-3.30 (m, 2H); 2.80-2.90 (m,2H); 1.75-1.85 (broad s, 1H).

Preparation 16 4-Trifluoromethylphenethyl alcohol ##STR50##

This was obtained by method described in Preparation 15 using4-trifluoromethylphenylacetic acid instead of(2,3-dihydrobenzofuran-5-yl)acetic acid as the starting material. Thetitle compound was obtained as a colourless oil, 3.75 g (80%), which wascharacterised by its ¹ H-N.M.R. spectrum.

¹ H-N.M.R. (CDCl₃) δ=7.59 (d, J=8Hz, 2H); 7.38 (d, J=8Hz, 2H); 3.94 (t,J=7Hz, 2H); 2.97 (t, J=7Hz, 2H); 1.62 (s, 1H).

We claim:
 1. A compound of the formula ##STR51## or a pharmaceuticallyacceptable salt thereof, wherein X is N or ##STR52## where R⁴ is H, haloor C₁ -C₄ alkyl;R¹ is H or C₁ -C₄ alkyl; R² is H or C₁ -C₄ alkyl; Y is adirect link, 0 or S; m is an integer of from 1 to 4; n is 2 or 3; and R³is 1- or 2-naphthyl or a group of the formula: ##STR53## where R⁵ and R⁶are each independently H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, --(CH₂)_(q) OH,halo, trifluoromethyl, cyano, --(CH₂)_(q) NR⁷ R⁸, --OCO(C₁ -C₄ alkyl),--SO₂ NH₂, --CONR⁹ R¹⁰ ;where either R⁷ and R⁸ are each independently Hor C₁ -C₄ alkyl, or R⁷ is H and R⁸ is --SO₂ (C₁ -C₄ alkyl), --CONR⁹ R¹⁰,--CO(C₁ -C₄ alkyl) or --SO₂ NH₂ ; R⁹ and R¹⁰ are each independently H orC₁ -C₄ alkyl; q is 0, 1 or 2; Z and Z¹ are each independently CH₂ oroxygen; p is 1, 2 or 3;with the proviso that when X is nitrogen, thenYR₃ cannot be unsubstituted phenyl.
 2. A compound as claimed in claim 1wherein R¹ is H, X is N or CH, m is 1, 2 or 3, n is 2, R² is methyl andY is a direct link or
 0. 3. A compound as claimed in claim 2 wherein R³is 2-naphthyl, or a group of the formula: ##STR54## where R⁵ and R⁶ areeach independently H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo,trifluoromethyl, cyano or C₁ -C₄ alkanesulphonamido, and Z¹ is 0 or CH₂.4. A pharmaceutical composition comprising a compound of the formula (I)as claimed in claim 1, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable diluent or carrier.
 5. A method oftreating irritable bowel syndrome in a patient in need of suchtreatment, characterised by administering to said patient an effectiveamount of a compound of the formula (I) or pharmaceutically acceptablesalt thereof as claimed in claim.
 6. A method of treating or preventingdiseases associated with altered motility and/or tone of smooth musclecomprising administering to a patient a muscarinic receptor antagonisteffective amount of a compound according to claim